Familial euthyroid thyroxine excess: characterization of abnormal intermediate affinity thyroxine binding to albumin.
The abnormal high capacity T4 binding site of familial euthyroid T4 excess was separable from prealbumin and T4-binding globulin but not from albumin. We therefore compared T4 binding by albumin preparations isolated from the sera of normal and affected subjects. By equilibrium dialysis, albumin from affected subjects showed an extra T4 binding site (Kd approximately 50 nM) in addition to the T4 binding sites of normal albumin (Kd approximately 4 microM). Comparison of the estimated capacity of the additional site (200 microM) with the molar concentration of albumin suggested that only about one third of albumin molecules from affected subjects contained the extra binding site. Estimates of affinity and capacity were used to derive combining powers for the diverse classes of serum T4 binding sites. From these estimates, it appears that the presence of the abnormal site accounts for the approximate doubling of normal mean total T4 (from approximately 100 nM or 7.7 micrograms/dl to approximately 200 nM or 15.5 micrograms/dl), in order to maintain a normal free T4 in the face of the increased T4 association with albumin. Studies of [125I]T4 displacement from albumin of affected subjects showed low T3 affinity and competition by barbitone. Relative molar concentrations to give equivalent displacement of [125I]T4 were: 3,3',5,5'-tetraiodothyroacetic acid, 0.4; T4, 1.0; rT3, 4; 8-anilinonaphthalene sulfonic acid, 10; T3, 80; salicylate, 200; and barbitone, 40,000. Studies with dithiothreitol suggested that disulfide bonds were critical in maintaining the T4-albumin association. These findings indicate that familial T4 excess is due to abnormal intermediate affinity, sulfhydryl-sensitive T4 binding sites that are inseparable from the albumin found in affected subjects.
D001462:Barbital / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D003956:Dialysis; D004229:Dithiothreitol / Q000494:pharmacology; D006801:Humans; D012709:Serum Albumin / Q000378:metabolism*; D013974:Thyroxine / Q000097:blood*; D013975:Thyroxine-Binding Proteins / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism
D012709:Serum Albumin; D013975:Thyroxine-Binding Proteins; D014284:Triiodothyronine; D001462:Barbital; D013974:Thyroxine; D004229:Dithiothreitol